The purpose of this project is to determine the basic metabolic defects that are responsible for the development of the primary hyperlipidemias. During the past few years at least 3 monogenetic disorders have been described that cause increases in plasma lipids (cholesterol and triglycerides). In the present work we intend to identify families with these different disorders and to study individual family members for the underlying causes of increased plasma lipids or lipoproteins. In these studies, turnover rates of cholesterol and different lipoproteins will be carried out simultaneously to determine whether there is an overproduction of lipids and lipoproteins by the liver or whether the basic defect resides in the removal of lipoproteins from the plasma compartment. During the past year we have attempted to improve on the methodology for measurement of turnover of lipoproteins. BIBLIOGRAPHIC REFERENCES: Stein, O., Weinstein, D.B., Stein, Y., and Steinberg, D.: Binding, Internalization and Degradation of Low Density Lipoprotein by normal Human Fibroblasts and by Fibroblasts from a Case of Homozygous Familial Hypercholesterolemia. PNAS (in press, January, 1976).